N,N-di(aryl) cyclic urea derivatives as anti-coagulants

ABSTRACT

N,N-di(aryl) cyclic urea derivatives, such as the compounds of the following formula: ##STR1## wherein R 1  is --C(NH)NH 2 , --C(NH)N(H)OR 11 , --C(NH)N(H)C(O)R 9 , or --C(NH)N(H)C(O)OR 11  ; 
     R 2  and R 3  are independently hydrogen, halo, lower alkyl, lower haloalkyl, aryl, --OR 11 , --C(O)OR 11 , --C(O)N(R 11 )R 12 , --N(R 11 )R 12 , --N(H)C(O)R 11 , or --N(H)S(O) 2  R 11  ; 
     R 4  is halo, lower haloalkyl, imidazolyl, --C (NH)NH 2 , --C(NH)NHOR 11 , --C(NH)N(H)C(O)R 9 , --C(NH)N(H)C(O)OR 11 , --OR 11 , --C(O)R 13 , --(CH 2 ) n  C(O)OR 11  (where n is 0 to 6), --C(O)N(R 11 )R 12 , or --N(R 11 )R 12  ; 
     R 7  and R 8  are independently hydrogen, lower alkyl, lower haloalkyl, 4-pyridinyl, --C(O)OR 11 , --C(O)N(R 11 )R 12 , or aryl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 ); 
     R 11  and R 12  are independently hydrogen, lower alkyl, aryl or lower aralkyl; or 
     R 13  is pyrrolidinyl, 4-morpholinyl, piperazinyl, N-methylpiperazinyl, or piperidinyl; or a pharmaceutically acceptable salt thereof, are disclosed herein as being inhibitors of factor Xa and thereby being useful as anticoagulants.

This is a Division of application Ser. No. 08/458,598, filed Jun. 2,1995, now U.S. Pat. No. 5,612,363.

FIELD OF THE INVENTION

The present invention is directed to N,N-di(aryl) cyclic ureaderivatives and their pharmaceutically acceptable salts, which inhibitthe enzymes in the coagulation cascade, such as factor Xa and factor IIa(thrombin), thereby being useful as anti-coagulants. It also relates topharmaceutical compositions containing the derivatives or theirpharmaceutically acceptable salts, and their methods of use.

BACKGROUND OF THE INVENTION

Factor Xa is a member of the trypsin-like serine protease class ofenzymes. A one-to-one binding of factors Xa and Va with calcium ions andphospholipid forms the prothrombinase complex which converts prothrombinto factor IIa (thrombin). Thrombin, in turn, converts fibrinogen tofibrin which polymerizes to form insoluble fibrin.

In the coagulation cascade, the prothrombinase complex is the convergentpoint of the intrinsic (surface activated) and extrinsic (vesselinjury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363;and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulationcascade has been refined further with the discovery of the mode ofaction of tissue factor pathway inhibitor (TFPI) (Seminars in HematoIogy(1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serineprotease inhibitor with three Kunitz-like domainms which competes withfactor Va for free factor Xa. Once formed, the binary complex of factorXa and TFPI becomes a potent inhibitor of the factor VIIa and tissuefactor complex.

Factor Xa can be activated by two distinct complexes, by tissuefactor-factor VIIa complex on the "Xa burst" pathway and by the factorIXa-VIIA complex (TENase) of the "sustained Xa" pathway in thecoagulation cascade. After vessel injury, the "Xa burst" pathway isactivated via tissue factor (TF). Up regulation of the coagulationcascade occurs via increased factor Xa production via the "sustained Xa"pathway. Down regulation of the coagulation cascade occurs with theformation of the factor Xa-TFPI complex, which not only removes factorXa but also inhibits further factor formation via the "Xa burst"pathway. Consequently, there is a natural regulation of the coagulationcascade by factor Xa.

Published data with the proteins antistasin and tick anti-coagulantpeptide (TAP) demonstrate that factor Xa inhibitors are efficaciousanti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp.371-376; and Science (1990), Vol. 248, pp. 593-596).

The active site of factor Xa can be blocked by either a mechanism-basedor a tight binding inhibitor (a tight binding inhibitor differs from amechanism-based inhibitor by the lack of a covalent link between theenzyme and the inhibitor). Two types of mechanism-based inhibitors areknown, reversible and irreversible, which are distinguished by ease ofhydrolysis of the enzyme-inhibitor link (Thrombosis Res (1992), Vol. 67,pp. 221-231; and Trends Pharmacol. Sci. (1987), Vol. 8, pp. 303-307). Aseries of guanidino compounds are examples of tight-binding inhibitors(Thrombosis Res. (1980), Vol. 19, pp. 339-349).Arylsulfonyl-arginine-piperidinecarboxylic acid derivatives have alsobeen shown to be tight-binding inhibitors of thrombin (Biochem. (1984),Vol. 23, pp. 85-90), as well as a series of arylamidine-containingcompounds, including 3-amidinophenylaryl derivatives (Thrombosis Res.(1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones(Thrombosis Res. (1980), Vol. 17, pp. 545-548). Therapeutic utility ofthese compounds, however, is limited by their poor selectivity forfactor Xa.

Related Disclosures

European Published Patent Application 0 540 051 (Nagahara et al.)describes aromatic amidine derivatives which are stated to be capable ofshowing a strong anticoagulant effect through reversible inhibition offactor Xa.

The synthesis of α,α'-bis(amidinobenzylidene)cycloalkanones andα,α'-bis(amidino-benzyl)cycloalkanones is described in Pharmazie (1977),Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as beingserine protease inhibitors.

SUMMARY OF THE INVENTION

This invention is directed to compounds or their pharmaceuticallyacceptable salts which are anti-coagulants by inhibiting enzymes in thecoagulation cascade, such as human factor Xa and factor IIa (thrombin),and are therefore useful as pharmacological agents for the treatment ofdisease-states characterized by thrombotic activity.

Accordingly, in one aspect, this invention provides compounds selectedfrom the group consisting of the following formulae: ##STR2## wherein Ais --C(R⁵)R⁶ --(CH₂)_(m) --C(R⁹)(R¹⁰)-- (where m is 0 to 2);

R¹ is --C(NH)NH₂, --C(NH)N(H)OR¹¹, --C(NH)N(H)C(O)R⁹, or--C(NH)N(H)C(O)OR¹¹ ;

R² and R³ are the same or different and are selected from the groupconsisting of hydrogen, halo, lower alkyl, lower haloalkyl, aryl,--OR¹¹, --C(O)OR¹¹, --C(O)N(R¹¹)R¹², --N(R¹¹)R¹², --N(H)C(O)R¹¹, and--N(H)S(O)₂ R¹¹ ;

R⁴ is halo, lower haloalkyl, imidazolyl, --C(NH)NH₂, C(NH)N(H)OR¹¹,--C(NH)N(H)C(O)R⁹, --C(NH)N(H)C(O)OR¹¹, --OR¹¹, --C(O)R¹³, --(CH₂)_(n)C(O)OR¹¹ (where n is 0 to 6), --C(O)N(R¹¹)R¹², or --N(R¹¹)R¹² ;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, halo, lower alkyl, lowerhaloalkyl, 4-pyridinyl, --OR¹¹, --C(O)OR¹¹, --C(O)N(R¹¹)R¹², or aryl(optionally substituted by one or more substituents selected from thegroup consisting of halo, hydroxy, lower alkyl, lower haloalkyl, loweralkoxy and --N(R¹¹)R¹²);

R⁷ and R⁸ are independently hydrogen, lower alkyl, lower haloalkyl,4-pyridinyl, --C(O)OR¹¹, --C(O)N(R¹¹)R¹², or aryl (optionallysubstituted by one or more substituents selected from the groupconsisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxyand --N(R¹¹)R¹²);

R¹¹ and R¹² are independently hydrogen, lower alkyl, aryl or loweraralkyl; or

R¹³ is pyrrolidinyl, 4-morpholinyl, piperazinyl, N-methylpiperazinyl, orpiperidinyl; or a pharmaceutically acceptable salt thereof.

In another aspect, this invention provides compositions useful intreating a human having a disease-state characterized by thromboticactivity, which composition comprises a therapeutically effective amountof a compound of the invention as described above, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, this invention provides a method of treating a humanhaving a disease-state characterized by thrombotic activity, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

In another aspect, this invention provides a method of treating a humanhaving a disease-state alleviated by the inhibition of factor Xa, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

In another aspect, this invention provides a method of treating a humanhaving a disease-state alleviated by the inhibition of factor IIa(thrombin), which method comprises administering to a human in needthereof a therapeutically effective amount of a compound of theinvention as described above.

In another aspect, this invention provides a method of inhibiting humanfactor Xa in vitro or in vivo by the administration of a compound of theinvention.

In another aspect, this invention provides a method of inhibiting humanfactor IIa (thrombin) in vitro or in vivo by the administration of acompound of the invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

"Halo" refers to bromo, chloro or fluoro.

"Lower alkyl" refers to a straight or branched chain monovalent radicalconsisting solely of carbon and hydrogen, containing no unsamration andhaving from one to four carbon atoms, e.g., methyl, ethyl, n-propyl,1-methylethyl (iso-propyl), n-butyl, 1,1-dimethylethyl (t-butyl), andthe like.

"Lower alkoxy" refers to a radical of the formula --OR_(a) where R_(a)is lower alkyl as defined above, e.g., methoxy, ethoxy, t-butoxy, andthe like.

"Lower haloalkyl" refers to a lower alkyl radical, as defined above,that is substituted by one or more halo radicals, as defined above,e.g., trifluoromethyl, difluoromethyl, trichloromethyl,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

"Aryl" refers to the phenyl or naphthyl radical.

"Aralkyl" refers to a radical of the formula --R_(a) R_(b) where R_(a)is lower alkyl as defined above and R_(b) is aryl as defined above,e.g., benzyl.

"Amidino" refers to the radical --C(NH)--NH₂.

"Benzamidine" refers to a phenyl radical substituted by an amidinoradical.

"Naphthamidine" refers to a naphthyl radical substituted by an amidinoradical.

"4-pyridinyl" refers to a pyridinyl radical attached at the 4-position.

"Factor IIa" refers to thrombin.

"Optional" or "optionally" means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, "optionally substituted aryl" means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

"Pharmaceutically acceptable salt" includes both acid and base additionsalts.

"Pharmaceutically acceptable acid addition salt" refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, andorganic acids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

"Pharmaceutically acceptable base addition salt" refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine,procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline and caffeine.

"Therapeutically effective amount" refers to that amount of a compoundof formula (I) which, when administered to a human in need thereof, issufficient to effect treatment, as defined below, for disease-statesalleviated by inhibition of factor Xa or factor IIa. The amount of acompound of formula (I) which constitutes a "therapeutically effectiveamount" will vary depending on the compound, the disease-state and itsseverity, and the age of the human to be treated, but can be determinedroutinely by one of ordinary skill in the art having regard to his ownknowledge and to this disclosure.

"Treating" or "treatment" as used herein cover the treatment of adisease-state in a human, which disease-state is alleviated byinhibition of factor Xa or by factor IIa; and include:

(i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it;

(ii) inhibiting the disease-state, i.e., arresting its development; or

(iii) relieving the disease-state, i.e., causing regression of thedisease-state.

The yield of each of the reactions described herein is expressed as apercentage of the theoretical yield.

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms in their structure. Thecompounds of the invention and their pharmaceutically acceptable saltsmay therefore exist as single stereoisomers, racemates, and as mixturesof enantiomers and diastereomers. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthis invention.

It is understood, for the purposes of this invention, that the compoundsof the invention do not include any combination of substituents that mayresult in unstable compounds.

The nomenclature used herein for the compounds of the invention isbasically a modified form of the I.U.P.A.C. system, wherein thecompounds are named as derivatives of benzamidine or naphthamidine.Accordingly, a compound of the invention selected from formula (III),i.e., ##STR3## wherein R¹ and R⁴ are both --C(NH)NH₂ ; R² and R³ areboth hydrogen; R⁷ and R⁸ are both phenyl; for example, a compound of thefollowing formula: ##STR4## is named herein as 3,3'-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!bis(benzamidine).

Utility and Administration

A. Utility

The compounds of the invention are inhibitors of factor Xa and factorIIa and therefore useful as anti-coagulants in treating disease-statescharacterized by thrombotic activity based on factor Xa's or factorIIa's role in the coagulation cascade (see Background of the Inventionabove). A primary indication for the compounds is prophylaxis for longterm risk following myocardial infarction. Additional indications areprophylaxis of deep vein thrombosis (DVT) following orthopedic surgeryor prophylaxis of selected patients following a transient ischemicattack. The compounds of the invention may also be useful forindications in which coumadin is currently used, such as for DVT orother types of surgical intervention such as coronary artery bypassgraft and percutaneous transluminal coronary angioplasty. The compoundsare also useful for the treatment of thrombotic complications associatedwith acute promyelocytic leukemia, diabetes, multiple myelomas,disseminated intravascular coagulation associated with septic shock,purpura fulminanas associated infection, adult respiratory distresssyndrome, unstable angina, and thrombotic complications associated withaortic valve or vascular prosthesis. The compounds are also useful forprophylaxis for thrombotic diseases, in particular in patients who havea high risk of developing such disease.

In addition, the compounds of the invention are useful as in vitrodiagnostic reagents for inhibiting factor Xa or factor IIa in thecoagulation cascade.

B. Testing

The primary bioassays used to demonstrate the inhibitory effect of thecompounds of the invention on factor Xa or factor IIa are simplechromogenic assays involving only serine protease, the compound of theinvention to be tested, substrate and buffer (see, e.g., Thrombosis Res.(1979), Vol. 16, pp. 245-254). For example, four tissue human serineproteases can be used in the primary bioassay, free factor Xa,prothrombinase, thrombin (factor IIa) and tissue plasminogen activator(tPA). The assay for tPA has been successfully used before todemonstrate undesired side effects in the inhibition of the fibrinolyticprocess (see, e.g., J. Med. Chem. (1993), Vol. 36, pp. 314-319).

Another bioassay useful in demonstrating the utility of the compounds ofthe invention in inhibiting factor Xa demonstrates the potency of thecompounds against free factor Xa in citrated plasma. For example, theanticoagulant efficacy of the compounds of the invention will be testedusing either the prothrombin time (PT), or activated partialthromboplastin time (aPTT) while selectivity of the compounds is checkedwith the thrombin clotting time (TCT) assay. Correlation of the K_(i) inthe primary enzyme assay with the K_(i) for free factor Xa in citratedplasma will screen against compounds which interact with or areinactivated by other plasma components. Correlation of the K_(i) withthe extension of the PT is a necessary in vitro demonstration thatpotency in the free factor Xa inhibition assay translates into potencyin a clinical coagulation assay. In addition, extension of the PT incitrated plasma can be used to measure duration of action in subsequentpharmacodynamic studies.

For further information on assays to demonstrate the activity of thecompounds of the invention, see R. Lottenberg et al., Methods inEnzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et al., ThrombosisResearch (1980), Vol. 19, pp. 579-588.

C. General Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally,topically, transdermally, or rectally, in the form of solid, semi-solid,lyophilized powder, or liquid dosage forms, such as for example,tablets, suppositories, pills, soft elastic and hard gelatin capsules,powders, solutions, suspensions, or aerosols, or the like, preferably inunit dosage forms suitable for simple administration of precise dosages.The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. Preferably, the composition will be about 5%to 75% by weight of a compound(s) of the invention, or apharmaceutically acceptable salt thereof, with the rest being suitablepharmaceutical excipients.

The preferred route of administration is oral, using a convenient dailydosage regimen which can be adjusted according to the degree of severityof the disease-state to be treated. For such oral administration, apharmaceutically acceptable composition containing a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, is formed bythe incorporation of any of the normally employed excipients, such as,for example, pharmaceutical grades of mannitol, lactose, stamh,pregelatinized starch, magnesium stearate, sodium saccharine, talcum,cellulose ether derivatives, glucose, gelatin, sucrose, titrate, propylgallate, and the like. Such compositions take the form of solutions,suspensions, tablets, pills, capsules, powders, sustained releaseformulations and the like.

Preferably such compositions will take the form of capsule, caplet ortablet and therefore will also contain a diluent such as lactose,sucrose, dicalcium phosphate, and the like; a disintegrant such ascroscarmellose sodium or derivatives thereof; a lubricant such asmagnesium stearate and the like; and a binder such as a starch, gumacacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, andthe like.

The compounds of the invention, or their pharmaceutically acceptablesalts, may also be formulated into a suppository using, for example,about 0.5% to about 50% active ingredient disposed in a carrier thatslowly dissolves within the body, e.g., polyoxyethylene glycols andpolyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc., a compound(s) of the invention(about 0.5% to about 20%), or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike, to thereby form a solution or suspension.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state alleviated by the inhibition of factor Xa inaccordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof the compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular disease-states, and the host undergoingtherapy. Generally, a therapeutically effective daily dose is from about0.14 mg to about 14.3 mg/kg of body weight per day of a compound of theinvention, or a pharmaceutically acceptable salt thereof; preferably,from about 0.7 mg to about 10 mg/kg of body weight per day; and mostpreferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day.For example, for administration to a 70 kg person, the dosage rangewould be from about 10 mg to about 1.0 gram per day of a compound of theinvention, or a pharmaceutically acceptable salt thereof, preferablyfrom about 50 mg to about 700 mg per day, and most preferably from about100 mg to about 500 mg per day.

Preferred Embodiments

Of the compounds of the invention as set forth above in the Summary ofthe Invention, several groups of compounds are preferred.

One preferred group is that group of compounds selected from formula (I)wherein R¹ is --C(NH)NH₂, --C(NH)N(H)OR¹¹ or --C(NH)N(H)C(O)OR¹¹ ; R²and R³ are each hydrogen; R⁴ is --C(NH)NH₂, --C(NH)N(H)OR¹¹ or--C(NH)N(H)C(O)OR¹¹ ; R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen,halo, or lower alkyl; and R¹¹ is hydrogen, lower alkyl, aryl or loweraralkyl.

Of this group of compounds, a preferred subgroup are those compoundswherein R¹ and R⁴ are each --C(NH)NH₂ ; and R⁵, R⁶, R⁹ and R¹⁰ areindependently hydrogen or halo.

Of this subgroup of compounds, a preferred class of compounds are thosecompounds wherein R⁵, R⁶, R⁹ and R¹⁰ are each chloro.

A preferred compound of this subgroup is 3,3'-(1,2-dihydro-2-oxo-4,5,6,7-tetrachloro-1H-benzimidazol-1,3-diyl)bis(methylene)!bis(benzamidine).

Another preferred group of compounds is that group of compounds selectedfrom the formula (III) wherein R¹ is --C(NH)NH₂, --C(NH)N(H)OR¹¹ or--C(NH)N(H)C(O)OR¹¹ ; R² and R³ are independently hydrogen, lower alkylor --OR¹¹ ; R⁴ is, --C(NH)NH₂, --C(NH)N(H)OR¹¹, --C(NH)C(H)C(O)OR¹¹, or--C(O)N(R¹¹)R¹² ; R⁷ and R⁸ are independently hydrogen, lower alkyl, oraryl (optionally substituted by one or substituerits selected from thegroup consisting of halo, hydroxy, lower alkyl, lower haloalkyl, loweralkoxy and --N(R¹¹)R¹²); and R¹¹ and R¹² are independently hydrogen,lower alkyl, phenyl or benzyl.

Of this group of compounds, a preferred subgroup of compounds is thatsubgroup wherein R¹ is --C(NH)NH₂ ; R² and R³ are independently hydrogenor --OR¹¹ ; R⁴ is --CO(NH)NH₂ or --C(O)N(R¹¹)R¹² ; R⁷ and R⁸ areindependently hydrogen, lower alkyl or phenyl (optionally substituted byone or moie substituents selected from the group consisting of --OR¹¹and --N(R¹¹)R¹²); and R¹¹ and R¹² are independently hydrogen or loweralkyl.

Of this subgroup of compounds, a preferred class of compounds is thatclass wherein R¹ and R⁴ are both --C(NH)NH₂ ; R² and R³ are bothhydrogen; R⁷ and R⁸ are independently phenyl optionally substituted by--OR¹¹ or --N(R¹¹)R¹² ; and R¹¹ and R¹² are independently hydrogen orlower alkyl.

Of this class of compounds a preferred subclass is that subclass ofcompounds wherein R⁷ and R⁸ are both phenyl.

Of this subclass of compounds, a preferred compound is 3,3'-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!bis(benzamidine).

Another preferred subclass of compounds from this class is that subclassof compounds wherein R⁷ is phenyl; and R⁸ is 4-dimethylaminophenyl.

Of this subclass of compounds, a preferred compound is 3,3'-2,3-dihydro-4-(4-dimethylaminophenyl)-2-oxo-5-phenyl-1H-imidazol-1,3-diyl!bis(methylene)!-bis(benzamidine).

Another preferred group of cormpounds is that group selected fromformula (IV) wherein R¹ and R⁴ are both --C(NH)NH₂ ; R² and R³ areindependently hydrogen or --OR¹¹ ; R⁷, R⁸ and R⁹ are independentlyhydrogen, lower alkyl or phenyl (optionally substituted by one or moresubstituents selected from the group consisting of --OR¹¹ and--N(R¹¹)R¹²); and R¹¹ and R¹² are independently hydrogen or lower alkyl.

Of this group of compounds, a preferred subgroup of compounds is thatsubgroup wherein R¹ and R⁴ are both --C(NH)NH₂ ; R² and R³ are bothhydrogen; R⁷ and R⁸ are both phenyl; and R⁹ is hydrogen.

Preferred compounds of this subgroup are 7- 3-4-(amidino)benzyl!-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl!methyl!-naphthalene-2-carboximidamideand 7- 3- 3-(amidino)benzyl!-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl!methyl!naphthalene-2-carboximidamide.

Another preferred group of compounds is that group selected from formula(V) wherein R¹ and R⁴ are both --C(NH)NH₂ ; R² and R³ are independentlyhydrogen or --OR¹¹ ; R⁷, R⁸, R⁹ and R¹⁰ are independently hydrogen,lower alkyl or phenyl (optionally substituted by one or moresubstituents selected from the group consisting of --OR¹¹ and--N(R¹¹)R¹²); and R¹¹ and R¹² are independently hydrogen or lower alkyl.

Of this group, a preferred subgroup of compounds is that subgroupwherein R¹ and R⁴ are both --C(NH)NH₂ ; R² and R³ are both hydrogen; R⁷and R⁸ are both phenyl; and R⁹ and R¹⁰ are both hydrogen.

A preferred compound of this subgroup is 7,7'-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl!bis(methylene)!bis(naphthalene-2-carboximidamide).

Preparation of Compounds of The Invention

As a matter of convenience, the following description of the preparationof the compounds of the invention is directed to the preparation ofcompounds of formula (III), although similar reagents and reactionconditions may be used to produced the other compounds of the invention.

A. Starting Materials

Compounds of formula (B) are starting materials in the prepration of thecompounds of the invention and are commercially available or may beprepared according to methods known to those skilled in the art, or maybe prepared as illustrated below in Reaction Scheme 1 wherein R¹⁴ andR¹⁵ are independently hydrogen or arylmethyl (where the aryl group issubstituted by a cyano group and optionally substituted by one or moresubstituents selected from the group consisting of halo, lower alkyl,lower haloalkyl, --OR¹¹, --C(O)OR¹¹, --C(O)N(R¹¹)R¹², --N(R¹¹)R¹²,--N(H)C(O)R¹¹ or --N(H)S(O)₂ R¹¹ where R¹¹ and R¹² are independentlyhydrogen, lower alkyl, aryl or lower aralkyl): ##STR5##

Compounds of formula (A) are commercially available, for example, fromAldrich Chemical Co., Inc., or made by prepared by methods known tothose of ordinary skill in the art.

In general, compounds of formula (B) are prepared by reacting a compoundof formula (A) with COCl₂ (phosgene) or a phosgene equivalent underbasic conditions, such as utilizing triethylamine under standardconditions to form the intermediate, R¹⁴ --N(H)═C═O!, which is thenreacted with a compound of formula R¹⁵ --NH₂ under standard conditionsto form a compound of formula (B).

B. Intermediates

1. Compounds of formula (Da) are intermediates in the preparation of thecompounds of the invention. They are prepared from compounds of formula(C) and formula (B) as illustrated below in Reaction Scheme 2 where R⁷and R⁸ are independently lower alkyl, lower haloalkyl, 4-pyrdinyl oraryl (optionally substituted by one or more substituents selected fromthe group consisting of halo, hydroxy, lower alkyl, lower haloalkyl,lower alkoxy and --N(R¹¹)R¹² wher R¹¹ and R¹² are independentlyhydrogen, lower alkyl, aryl or lower aralkyl); and R¹⁴ and R¹⁵ areindependently hydrogen or arylmethyl (where the aryl group issubstituted by cyano and optionally substituted by one or moresubstituents selected from the group consisting of halo, lower alkyl,lower haloalkyl, --OR¹¹, --C(O)OR¹¹, --C(O)N(R¹¹)R¹², --N(R¹¹)R¹²,--N(H)C(O)R¹¹ or --N(H)S(O)₂ R¹¹ (where R¹¹ and R¹² are independentlyhydrogen, lower alkyl, aryl or lower aralkyl)): ##STR6##

Compounds of formula (C) may be commercially available or prepared fromthe appropriate compounds, such as aldehydes, according to methods knownto those of ordinary skill in the art.

In general, a compound of formula (Da) are prepared by reacting acompound of formula (C) with a compound of formula (B) under acidicconditions, such as in refluxing acetic acid. The compound of formula(Da) is then isolated from the reaction mixture by standard techniques,such as crystallization or chromatography.

2. Compounds of formula (Fa) are also intermediates in the preparationof the compounds of the invention. They are prepared from compounds offormula (Db), and from formula (E) as illustrated below in ReactionScheme 3 where X is chloro, bromo or iodo; R² is hydrogen, halo, loweralkyl, lower haloalkyl, aryl, --OR¹¹, --C(O)OR¹¹, --N(R¹¹)R¹²,--N(H)C(O)R¹¹ or --N(H)S(O)₂ R¹¹ ; R³ is hydrogen, halo, lower alkyl,lower haloalkyl, aryl, or --OR¹¹ ; R⁷ and R⁸ are independently hydrogen,lower alkyl, lower haloalkyl, --C(O)OR¹¹, --C(O)N(R¹¹)R¹², or aryl(optionally substituted by one or more substituents selected from thegroup consisting of halo, --OR¹¹, lower alkyl, lower haloalkyl and--N(R¹¹)R¹²); where each R¹¹ and R¹² are independently hydrogen, loweralkyl, aryl or lower aralkyl: ##STR7##

Compounds of formula (Db) may be prepared according to the methoddescribed in Reaction Scheme 2 above for a compound of formula (Da)where R¹⁴ and R¹⁵ are hydrogen, or by methods known to those of ordinaryskill in the art. Compounds of formula (E) may be commercially availableor prepared by methods known to those of ordinary skill in the art.

In general, a compound of formula (Fa) are prepared by reacting acompound of formula (Db) with two or more molar equivalent amounts of acompound of formula (E) under standard alkylation conditions to preparea compound of formula (Fa). The compound of formula (Fa) is thenisolated from the reaction mixture by standard techniques, such ascrystallization or chromatography.

3. Compounds of formula (L) are also intermediates in the preparation ofcompounds of the invention. They are prepared as illustrated below inReaction Scheme 4 wherein X is bromo, chloro, iodo; R² is hydrogen,halo, lower alkyl, lower haloalkyl, aryl, --OR¹¹, --C(O)OR¹¹,--N(R¹¹)R¹², --N(H)C(O)R¹¹ or --N(H)S(O)₂ R¹ ; R⁷ and R⁸ areindependently hydrogen, lower alkyl, lower haloalkyl, --C(O)OR¹¹,--C(O)N(R¹¹)R¹², or aryl (optionally substituted by one or moresubstituents selected from the group consisting of halo, --OR¹¹, loweralkyl, lower haloalkyl and --N(R¹¹)R¹²), where each R¹¹ and R¹² areindependently hydrogen, lower alkyl, aryl or lower aralkyl; and each R¹⁶is lower alkyl, aryl or lower aralkyl: ##STR8##

Compounds of formula (Db) may be prepared according to the methoddescribed in Reaction Scheme 2 above, or by methods known to those ofordinary skill in the art.

Compounds of formula (G) and formula (E) may be commercially availableor prepared by methods known to those of ordinary skill in the art.

In general, compounds of formula (L) are prepared by first treating acompound of formula (Db) with a compound of formula (G) as a limitingreagent under standard alkylation conditions, for example, in an aproticsolvent in the presence of a base such as sodium hydride at temperaturesbetween about 20° C. to about 50° C., preferably at about 50° C., toyield a compound of formula (H). The compound of formula (H) is thentreated with one molar equivalent amount of a compound of formula (E)under similar alkylation condtions, to yield a compound of formula (J).The compound of formula (J) is then hydrolyzed under standard basichydrolysis conditions to yield a compound of formula (K) , which is thentreated with the appropriate amine under standard conditions to yield acompound of formula (L).

C. Preparation of the Compounds of the Invention

The following Reaction Scheme is illustrative of the preparation ofcompounds of the invention, particularly those of formula (III) asdescribed above in the Summary of the Invention, but similar reagentsand reaction conditions may be used to prepared compounds of the otherformulae.

Compounds of formula (IIIa) are compounds of the invention and areprepared as described below in Reaction Scheme 5 wherein R², R³, R⁷ andR⁸ are the same as described above in the Summary of the Invention:##STR9##

Compounds of formula (Fb) may be prepared according to the methodsdescribed above for compounds of formula (Fa).

In general, a compound of formula (IIIa) is prepared by first dissolvinga compound of formula (Fb) in a lower alkanol, preferably ethanol, andthen treating the solution overnight at around 0° C. with an anhydrousmineral acid, preferably HCl. The solvent is then removed and theresulting residue dissolved in fresh lower alkanol, preferably ethanol.The resulting solution is then treated with anhydrous ammonia attemperatures from between ambient temperatures and 100° C. from about 1to about 5 hours. The above reactions are carried out in high-pressureglass tubes and vessels. The compound of formula (IIIa) is then isolatedfrom the reaction mixture by standard techniques.

In the following Reaction Scheme, compounds of formula (IIIb), which arealso compounds of the invention, are similarly prepared from compoundsof formual (L), as illustrated below in Reaction Scheme 6, where R², R⁴,R⁷ and R⁸ are as described above in the Summary of the Invention:##STR10##

Compounds of formula (L) may be prepared according to the methodsdescribed above in Reaction Scheme 4.

Compounds of formulae (IIIa) and (IIIb) wherein R⁷ or R⁸ is --C(O)OR¹¹(where R¹¹ is lower alkyl) may be further hydrolyzed to producecompounds of the invention where R⁷ or R⁸ is C(O)OR¹¹ where R¹¹ ishydrogen. Such compounds may be further amidated to produce compounds ofthe invention wherein R⁷ or R⁸ are --C(O)N(R¹¹)R¹² (where R¹¹ and R¹²are hydrogen, lower alkyl, aryl or lower aralkyl).

Compounds of formulae (IIIa) and (IIIb) may be further treated with acidhalides, preferably acid chlorides, or with acid anhydrides orequivalents, to yield compounds of the invention where R¹ and R⁴ are--C(NH)N(H)C(O)R¹¹. Alternatively, compounds of formulae (IIIa) and(IIIb) may be further treated with carbamoyl chlorides, or theirequivalents, to yield compounds of the invention where R¹ and R⁴ are--C(NH)N(H)C(O)OR¹¹.

Compounds of the invention (as described above in the Summary of theInvention) wherein R¹ or R⁴ are --C(NH)N(H)OR¹¹ are prepared by treatinga compound of formulae (Fa), (Fb), (J), (K) and (L), as described above,with hydroxylamines of the formula R¹¹ ONH₂ (where R¹¹ is as describedabove in the Summary of the Invention) under basic conditions,preferably in the presence of triethylamine.

In summary, compounds of the invention, as illustrated above by thepreparation of compounds of formula (III), are prepared by:

(1) treating a compound of formula (C) with a compound of formula (B) toyield a compound of formula (Da); or

(2) treating a compound of formula (Db) with a compound of formula (E)to yield a compound of formula (Fa); or

(3) treating a compound of formula (Db) with a compound of formula (G)to yield a compound of formula (H); and then treating the compound offormula (H) with a compound of formula (E) to yield a compound offormula (J); and then treating the compound of formula (J) to yield acompound of formula (K); and then treating the compound of formula (K)to yield a compound of formula (L); and

(4) treating a compound of formulae (Da), (L) , (Fa) or (Fb) to form acompound of formula (III).

In addition, all compounds of the invention that exist in free base formor free acid form may be converted to their pharmaceutically acceptablesalts by treatment with the appropriate inorganic or organic acid, or bythe appropriate inorganic or organic base by methods known to those ofordinary skill in the art. Salts of the compounds of the invention canalso be converted to the free base form or to the free acid form or toanother salt by known methods.

The following specific preparations and examples are provided as a guideto assist in the practice of the invention, and are not intended as alimitation on the scope of the invention.

PREPARATION 1 4,4'-(2-Oxoimidazolin-1,3-diyl)bis(methylene)!bis(benzonitrile)

A. To sodium hydride (2.4 g, 60 mmol) in dimethylformamide (50 mL) at 0°C. was added imidazolin-2-one (2.6 g, 30 mmol). After stirring for 20minutes 4-(bromomethyl)benzonitrile (13 g, 66 mmol) was added and themixture was warmed to ambient temperature. After stirring for 1 hour thereaction was poured into water and a solid formed. The solid was riteredto give 4,4'-(2-oxoimidazolin-1,3-diyl)bis(methylene)!-bis(benzonitrile). NMR (CDCl₃)7.65 (d,4), 7.4 (d,4), 4.45 (s,4), 3.2 (s,4) ppm.

B. In a similar manner, the following compounds were made:

4,4'-(1,2,3,4,5,6-hexahydro-2-oxopyrimidin-1,3-diyl)bis(methylene)!bis(benzonitrile);NMR (CDCl₃) 7.63 (d,4), 7.4 (d,4), 3.25 (m,4), 4.62 (s,4), 3.25 (m,4),1.97 (m,2) ppm;

3,3'- (2-oxoimidazolin-1,3-diyl)bis(methylene)!bis(benzonitrile); NMR(CDCl₃) 7.6 (m,6), 7.47 (m,2), 4.45 (s,4), 3.23 (s,4) ppm;

3,3'-(2-oxo-4,4,5,5-tetramethylimidazolin-1,3-diyl)bis(methylene)!bis(benzonitrile);NMR (CDCl₃) 7.62 (m,4), 7.55 (d,2), 7.44 (t,2), 4.38 (s,4), 1.05 (s,12)ppm;

4,4'-(2-oxo-4,4,5,5-tetramethylimidazolin-1,3-diyl)bis(methylene)!bis(benzonitrile);NMR (CDCl₃) 7.65 (d,4), 7.55 (d,4), 4.4 (s,4), 1.1 (s,12) ppm;

1,3-bis(3-cyanobenzyl)-1,2-dihydro-5-ethyl-2-oxo-1H-imidazole-4-carboxylicacid, methyl ester; NMR (CDCl₃) 7.4-7.7 (m,8), 5.3 (s,2), 5.0 (s,2),3.79 (s,3), 2.7 (q,2), 1.04 (t,3) ppm;

1,3-bis(3-cyanobenzyl)-1,2-dihydro-2-oxo-1H-imidazole-4,5-dicarboxylicacid, diethyl ester; NMR (CDCl₃) 7.6 (m,6), 7.45 (m,2), 5.15 (s,4), 4.24(q,4), 1.25 (t,6) ppm;

3,3'-(2,3-dihydro-4-methyl-2-oxo-5-phenyl-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);NMR (CDCl₃) 7.1-7.6 (m, 13), 5.0 (s,2), 4.87 (s,2), 1.95 (s,6) ppm;

3,3'-(2,3-dihydro-4-ethyl-2-oxo-5-phenyl-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);NMR (CDCl₃) 7.5-7.7 (m,4), 7.3-7.5 (m,6), 7.2 (s,1), 7.15 (m,2), 5.02(s,2), 4.83 (s,2), 2.3 (q,2), 0.95 (t,6) ppm;

3,3'-(4,5-bis(methylethyl)-2,3-dihydro-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);NMR (CDCl₃) 7.56 (m,2), 7.5 (m,8), 5.03 (s,4), 2.95 (m,2), 1.13 (d,12)ppm;

3,3'-(4,5-diethyl-2,3-dihydro-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);NMR (CDCL₃) 7.6 (m,2), 7.58 (m,8), 4.95 (s,4), 2.3 (q,4), 1.0 (t,6) ppm;and

3,3'-(2,3-dihydro-4,5-dimethyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);NMR (CDCl₃) 7.6 (m,2), 7.5 (m,8), 4.93 (s,4), 1.9 (s,6) ppm.

PREPARATION 2 4,4'-(1,2-Dihydro-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!bis(benzonitrile)

A. To dimethylformamide (50 mL) was added 2-hydroxy-1H-benzimidazole(2.7 g, 25 mmol), cesium carbonate (17 g, 55 mmol), and4-(bromomethyl)benzonitrile (10 g, 50 mmol). After stirring for 3 hours,the mixture was poured into water. The precipitate was filtered andwashed with water. The solid was dissolved in ethyl acetate, dried (Na₂SO₄), treated with charcoal, and the solvent was removed in vacuo togive 4,4'-(1,2-dihydro-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!bis(benzonitrile);NMR (CDCl₃) 7.85 (d,4), 7.6 (d,4), 7.2 (m,2), 7.1 (m,2), 5.25 (s,4) ppm.

B. In a similar manner, the following compounds were made:

3,3'-(1,2-dihydro-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!bis(benzonitrile);NMR (CDCl₃) 7.6 (m,6), 7.48 (m,2), 7.07 (m,2), 6.89 (m,2), 5.15 (s,4)ppm;

4,4'-(1,2-dihydro-4-methyl-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);NMR (CDCl₃) 7.65 (d,4), 7.44 (d,2), 7.28 (d,2), 6.95 (t,1), 6.83 (d,1),6.75 (d,1), 5.4 (s,2), 5.18 (s,2), 2.3 (s,3) ppm;

4,4'-(1,2-dihydro-4,7-dimethyl-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);

3,3'-(1,2-dihydro-4-methyl-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);NMR (CDCl₃) 7.6 (m,4), 7.44 (m,2), 6.98 (t,2), 6.83 (d,1), 6.77 (d,1),5.4 (s,2), 5.18 (s,2), 2.33 (s,3) ppm;

3,3'-(1,2-dihydro4,7-dimethyl-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);NMR (CDCl₃) 7.6 (m,2), 7.45 (m,6), 6.72 (s,2), 5.43 (s,4), 2.33 (s,6)ppm;

3,3'-(5,6-dichloro-1,2-dihydro-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);

3,3'-2,3-dihydro-4-(4-dimethylaminophenyl)-2-oxo-5-phenyl-1H-imidazol-1,3-diyl!bis(methylene)!bis(benzonitrile);NMR (CDCl₃) 7.3-7.6 (m,6), 7.24 (m,5), 7.03 (m,2), 6.85 (d,2), 6.53(d,2), 4.9 (s,2), 4.86 (s,2), 2.95 (s,6) ppm;

3,3'-2,3-dihydro-4,5-bis(4-methoxyphenyl)-2-oxo-1H-imidazol-1,3-diyl!bis(methylene)!-bis(benzonitrile);

7,7'-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!-bis(naphthalene-2-carbonitrile);

4,4'-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);

3,3'-(2,3-dihydro-2-oxo-4-phenyl-1H-imidazol-1,3-diyl)bis(methylene)!bis(benzonitrile);NMR (CDCl₃) 7.4-7.6 (m,5), 7.24 (m,5), 7.03 (m,3), 6.13 (s,1), 4.85(s,2), 4.83 (s,2) ppm;

3,3'-(1,2-dihydro-2-oxo-4,5,6,7-tetrachloro-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzenecarbonitrile);NMR (CDCl₃) 7.6 (m,2), 7.48 (m,6), 5.6 (s,4) ppm;

3,3'-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);and

4,4'-(1,2-dihydro-2-oxo-4,5,6,7-tetrachloro-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzonitrile);NMR (CDCl₃) 7.65 (m,4), 7.33 (m,4), 5.6 (s,4) ppm.

PREPARATION 34-(4-Dimethylaminophenyl)-2,3-dihydro-5-phenyl-1H-imidazol-2-one

A. To acetic acid (2 mL) was added urea (0.6 g, 10 mmol) and2-(4-dimethyl-aminophenyl)-2-hydroxy-1-phenylethanone (2.6 g, 10 mmol).After stirring for 2 hours at 120° C., the reaction was cooled toambient temperature. The resulting solid was filtered, washed withether, and dried in vacuo to give4-(4-dimethylaminophenyl)-2,3-dihydro-5-phenyl-1H-imidazol-2-one; NMR(CDCl₃) 10.98 (s,2), 7.5 (m,4), 7.4 (m,5), 3.18 (s, 6) ppm.

B. In a similar manner, the following compounds were made:

4,5-bis(4-methoxyphenyl)-2,3-dihydro-1H-imidazol-2-one; NMR (DMSO-d6)11.0 (s,2), 7.62 (d, 1), 7.26 (d,4), 6.9 (d,4), 3.73 (s,6) ppm;

2,3-dihydro-4-ethyl-5-phenyl-1H-imidazol-2-one; NMR (DMSO-d6) 11.02 (s,1), 10.98 (s,1), 7.4 (m,4), 7.3 (m, 1), 2,5 (m,2), 1.2 (t,3) ppm; and

4,5-diethyl-2,3-dihydro-1H-imidazol-2-one; NMR (DMSO-d₆) 9.5 (s,2), 2.22(q,4), 1.05 (t,6) ppm.

PREPARATION 4 3-(2,3-Dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrile

A. In a manner similar to Preparation 1 above,2,3-dihydro4,5-diphenyl-1H-imidazol-2-one (1.2 g, 5 mmol) was reactedwith 3-(bromomethyl)benzonitrile (0.39 g, 2 mmol) and sodium hydride(0.18 g, 5 mmol) in dimethylformamide (20 mL) to give 3-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrileafter chromatography on silica; NMR (DMSO-d₆) 11.02 (s,1), 7.4 (m,4),7.3 (m,2), 7.2 (m,7), 4.75 (s,2) ppm.

B. In a similar manner, the following compound was made:

4- (2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrile;NMR (DMSO-d₆) 11.02 (s,1), 7.67 (d,2), 7.4 (m,3), 7.2 (m,9), 4.75 (s,2)ppm.

PREPARATION 52-(3-methoxycarbonylphenyl)methyl-dihydro-4,5-diphenyl-1H-imidazoI-2-one

A. To 2,3-dihydro-4,5-diphenyl-1H-imidazol-2-one (4.76 g, 20 mmol) in 50mL DMF was added to a suspension of NaH (0.8 g, 20 mmol) in 25 mL DMF.The suspension was stirred at ambient temperatures for 30 minutes, thenheated to 50° C. for 30 minutes. A solution of methyl3-bromomethylbenzoate (2.86 g, 12.5 mmol) in 20 mL DMF was then addedand the reaction stirred for 10 min at 50° C. The mixture was pouredinto 1N HCl, filtered, washed with water and dried. Chromatography onsilica gel (2% EtOH in 7:3 methylene chloride/ethyl acetate) afforded1.2 g of3-(3-methoxycarbonylphenyl)methyl-4,5-diphenyl-1H-imidazol-2-one as awhite solid.

B. In a similar manner, the following compounds are made:

3-(3-ethoxycarbonylphenyl)methyl-4,5-diphenyl-1H-imidazol-2-one;

3-(3-phenoxycarbonylphenyl)methyl-4,5-diphenyl-1H-imidazol-2-one; and

3-(3 -benzyloxycarbonylphenyl)methyl-4,5-diphenyl-1H-imidazol-2-one.

PREPARATION 6 7-3-(3-Cyanophenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl!methyl!naphthalene-2-carbonitrile

A. In a manner similar to Preparation 2 above, 3-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrile wasreacted with 7-(bromomethyl)-naphthalene-2-carbonitrile to give 7-3-(3-cyanophenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl!methyl!naphthalene-2-carbonitrile;NMR (CDCl₃) 8.05 (s,1), 7.9 (d,1), 7.85 (d,1), 7.55 (m,3), 7.4 (m,2),7.2 (m,9), 7.0 (m,3), 5.1 (s,2), 4.95 (s,2) ppm.

B. In a similar manner, the following compounds were made:

7-3-(4-cyanophenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl!methyl!-naphthalene-2-carbonitrile;NMR (CDCl₃) 8.05 (s,1), 7.85 (d,1), 7.8 (d,1), 7.55 (m,3), 7.45 (d,1),7.4 (s,1), 7.2 (m,8), 7.0 (m,4), 5.1 (s,2), 5.0 (s,2) ppm; and

3,4-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl!bis(methylene)!-bis(benzonitrile).

PREPARATION 7 3-(3-(3-methoxycarbonylphenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrile

A. In a manner similar to Preparation 2 above, a suspension of2-(3-methoxycarbonylphenyl)methyl-dihydro-4,5-diphenyl-1H-imidazol-2-one(410 mg, 1.1 mmol) (as prepared above in Preparation 5), cesiumcarbonate (1.5 g) and 4-methoxy-3-bromomethylbenzonitrile (0.2 g, 1mmol) in 2 mL DMF was stirred at ambient temperature for 3 hours. Themixture was poured into 50 mL water and extracted with ethyl acetate(3×50 mL). The ethyl acetate layer was washed with water, dried andevaporated to afford 0.55 g of 4-methoxy-3-(3-(3-methoxycarbonyl-phenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrileas a white solid.

B. To the ester formed above (0.5 g) in 5 mL MeOH was added 5 mL of 25%NaOH and the reaction stirred at ambient temperatures for 30 minutes.The reaction was acidified to pH 4 with 1N HCl and extracted with ethylacetate (3×50 mL). The ethyl acetate layer was dried and evaporated toafford 0.4 g of the acid, 4-methoxy-3-(3-(3-carboxyphenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrileas a white solid.

PREPARATION 8 3-(3-(3-dimethylaminocarbonylphenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrile

A. To a solution of 4-methoxy-3-(3-(3-carboxyphenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrile(0.39 g, 0.72 mmol), as prepared above in Preparation 7, in 5 mL DMF wasadded N,N-carbonyldiimidazole (166 mg, 1 mmol) and the reaction stirredat ambient temperatures for 2 hours. Dimethylamine (0.5 mL of 2Msolution in THF) was added and the reaction stirred 10 h at ambienttemperatures. The reaction mixture was poured into 50 ml. 1N HCl andextracted with EtOAc. The organic layer was washed with water, dried andevaporated to afford 0.17 g of 4-methoxy-3-(3-(3-dimethylaminocarbonylphenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrileas a white solid.

EXAMPLE 1 4,4'-(2-Oxoimidazolin-1,3-diyl)bis(methylene)!bis(benzamidine),Dihydrochloride

A. To 4,4'- (2-oxoimidazolin-1,3-diyl)bis(methylene!bis(benzonitrile)(5g, 16 mmol) in ethanol (20 mL) and methylene chloride (20 mL) at 0° C.was bubbled hydrochloric acid (g). After sealing the reaction vessel andstirring in a high-pressure flask for 16 hours, the reaction mixture waspoured into ether to obtain a solid. The solid was collected byfiltration and washed with ether. To the solid was added ethanol (40 mL)and the mixture was cooled to 0° C. Ammonia was bubbled into thereaction mixture. After sealing the reaction vessel, and heating at 55°C. for 4 hours, the mixture was cooled, poured into ether and the solidwas collected by filtration. Recrystallization from ethanol gave 4,4'-(2-oxoimidazolin-1,3-diyl)bis(methylene)!bis(benzamidine)dihydrochloride. Further purification by high performance liquidchromatography (HPLC) was sometimes necessary to give the final product.In such instances, the dihydrochloride salt was often replaced bytrifluoroacetic acid (TFA) salt; NMR (DMSO-d₆) 9.3 (s,4), 9.0 (s,4), 7.8(d,4), 7.5 (d,4), 4.45 (s,4), 3.25 (s,4) ppm.

B. In a similar manner, the following compounds were made:

3,3'-(1,2-dihydro-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.35 (s,4), 9.0 (s,4), 7.8 (s,2), 7.7(m,4), 7.55 (t,2), 7.1 (m,2), 7.0 (m,2), 5.2 (s,4) ppm;

4,4'-(1,2-dihydro-4-methyl-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.3 (s,4), 9.0 (s,4), 7.8 (d,4), 7.55(d,2), 7.35 (d,2), 7.0 (d,1), 6.9 (t,1), 6.75 (t,1), 5.43 (s,2), 5.22(s,2), 2.25 (s,3) ppm;

4,4'-(1,2,3,4,5,6-hexahydro-2-oxopyrimidin-1,3-diyl)bis(methylene)!bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.3 (s,4), 9.0 (s,4), 7.8 (d,4), 7.5(d,2), 4.6 (s,4), 3.25 (m,4), 1.9 (m,2) ppm;

4,4'-(1,2-dihydro-4,7-dimethyl-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.35 (s,4), 9.05 (s,4), 7.82 (d,4), 7.4(d,2), 6.7 (s,2), 5.5 (s,4), 2.25 (s,6) ppm;

3,3'-(1,2-dihydro-4-methyl-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.3 (br,8), 7.6-7.9 (m,6), 7.45 (d,2),7.05 (d,1), 6.95 (t,1), 6.8 (t,1), 5.43 (s,2), 5.25 (s,2), 2.3 (s,3)ppm;

3,3'-(1,2-dihydro-4,7-dimethyl-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.35 (s,4), 8.95 (s,4), 7.2-7.8 (m,8),6.65 (s,2), 5.45 (s,2), 5.4 (s,2), 2.25 (s,3) ppm;

3,3'-(5,6-dichloro-1,2-dihydro-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.38 (s,4), 9.05 (s,4), 7.8 (s,2), 7.72(m,4), 7.6 (t,2), 7.5 (s,2), 5.2 (s,4) ppm;

1,3-bis3-(amidino)benzyl!1,2-dihydro-5-ethyl-2-oxo-1H-imidazole-4-carboxylicacid, methyl ester, dihydrochloride; NMR (DMSO-d₆) 9.4 (s,4), 9.15(s,2), 9.05 (s,2), 7.73 (m,4), 7.58 (m,4), 5.25 (s,2) 5.1 (s,2), 3.7(s,3), 2.75 (q,2), 0.97 (t,3) ppm;

3,3'-(4,5-diethyl-2,3-dihydro-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.4 (s,4), 9.1 (s,4), 7.7 (m,4), 7.58(t,2), 7.44 (d,2), 4.95 (s,4), 2.35 (q,4), 0.9 (t,6) ppm;

1,3-bis3-(amidino)benzyl!-1,2-dihydro-2-oxo-1H-imidazole-4,5-dicarboxylic acid,diethyl ester, dihydrochloride; NMR (DMSO-d₆) 9.35 (s,4), 9.05 (s,4),7.7 (m,4), 7.58 (m,4), 5.2 (m,4), 4.18 (q,4), 1.15 (t,6) ppm;

4,4'-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆)9.3 (s,4), 9.1 (s,4), 7.78(d,4), 7.25 (m,10), 7.2 (m,4), 4.98 (s,4) ppm;

3,3'-(2,3-dihydro-2-oxo-4-phenyl-1H-imidazol-1,3-diyl)bis(methylene)!bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (s,2), 9.3 (s,2), 9.05(s,2), 9.0 (s,2), 7.4-7.8 (m,9), 7.3 (m,9), 6.88 (s,1), 5.03 (s,2), 4.97(s,2) ppm;

3,3'-(2,3-dihydro-4-methyl-2-oxo-5-phenyl-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.38 (s,2), 9.3 (s,2), 9.05(s,2), 9.0 (s,2), 7.2-7.8 (m,13), 5.01 (s,2), 4.9 (s,2), 2.0 (s,3) ppm;

3,3'-2,3-dihydro-4-(4-dimethylaminophenyl)-2-oxo-5-phenyl-1H-imidazol-1,3-diyl!bis(methylene)!bis(benzamidine),trifluoroacefic acid salt; NMR (DMSO-d₆) 9.3 (s,4), 9.03 (s,2), 9.0(s,2), 7.65 (m,2), 7.5 (m,4), 7.25 (m, 11), 4.95 (s,4), 3.03 (s,6) ppm;

3,3'-2,3-dihydro-4,5-bis(4-methoxyphenyl)-2-oxo-1H-imidazol-1,3-diyl!bis(methylene)!-bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,4), 9.03 (s,4), 7.65(d,2), 7.52 (m,4), 7.32 (d,2), 7.08 (d,4), 6.9 (d,4), 4.9 (s,4), 3.7(s,6) ppm;

7- 3-3-(amidino)benzyl!-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl!methyl!-naphthalene-2-carboximidamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.45 (s,2), 9.35 (s,2), 9.15(s,2), 9.05 (s,2), 8.4 (s,1), 8.1 (d,1), 7.98 (d,1), 7.8 (d,1), 7.66(m,2), 7.55 (m,2), 7.45 (d, 1), 7.35 (d,1), 7.2 (m,10), 5.05 (s,2), 5.0(s,2) ppm;

7- 3-4-(amidino)benzyl!-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl!methyl!-naphthalene-2-carboximidamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.4 (s,2), 9.25 (s,2), 9.1(s,2), 9.0 (s,2), 8.4 (s,1), 8.05 (d,1), 7.98 (d,1), 7.75 (m,3), 7.65(s,1), 7.4 (d,1), 7.2 (m,12), 5.05 (s,2), 5.0 (s,2) ppm;

7,7'-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl!bis(methylene)!-bis(naphthalene-2-carboximidamide),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.4 (s,4), 9.1 (s,4), 8.4(s,2), 8.1 (d,2), 8.0 (d,2), 7.8 (d,2), 7.68 (s,2), 7.45 (d,2), 7.2 (m,10), 5.1 (s,4) ppm;

3,3'-2,3-dihydro-4-ethyl-2-oxo-5-phenyl-1H-imidazol-1,3-diyl!bis(methylene)!-bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.36 (s,2), 9.3 (s,2), 9.05(s,2), 9.0 (s,2), 7.78 (s,1), 7.75 (d,1), 7.4-7.7 (m,5), 7.37 (m,3),7.23 (m,3), 5.02 (s,2), 4.85 (s,2), 2.35 (q,2), 0.92 (t,3) ppm;

3,3'-4,5-bis(methylethyl)-2,3-dihydro-2-oxo-1H-imidazol-1,3-diyl!bis(methylene)!-bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.38 (s,4), 9.07 (s,4), 7.7(m,4), 7.6 (t,2), 7.3 (m,2), 5.02 (s,2), 5.03 (s,4), 3.0 (m,2), 1.1(d,12) ppm;

3,4-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazo1-1,3-diyl!bis(methylene)!-bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.28 (s,2), 9.0(s,4), 7.73 (d,2), 7.66 (d,1), 7.5 (m,2), 7.25 (m,9), 7.18 (m,4), 4.98(s,2), 4.95 (s,2) ppm;

3,3'-(1,2-dihydro-2-oxo-4,5,6,7-tetrachloro-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.38 (s,4), 9.1 (s,4), 7.7 (m,4), 7.6(m,4), 5.58 (s,4) ppm;

4,4'-(1,2-dihydro-2-oxo-4,5,6,7-tetrachloro-1H-benzimidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),dihyclrochloride; NMR (DMSO-d₆) 9.20 (s,4), 8.80 (s,4), 7.80 (d,4), 7.40(d,4), 5.60 (d,4) ppm;

3-(3-((3-aminocarbonyl)phenyl)methyl-2,3-dihydro-4-ethyl-2-oxo-5-phenyl-1H-imidazol-1-yl)methyl)benzamidine,trifluoroacetic acid salt;

3-(3-((3-aminocarbonyl)phenyl)methyl-2,3-dihydro-5-ethyl-2-oxo-4-phenyl-1H-imidazol-1-yl)methyl)benzamidine,trifluoroacetic acid salt;

3-(3-((3-aminocarbonyl)phenyl)methyl-2,3-dihyclro-4,5-bis(4-methoxyphenyl)-2-oxo-1H-imidazol-1-yl)methyl)benzamidine,trifluoroacetic acid salt;

3-(3-(3-amidino-6-hydroxy)benzyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)-methyl!benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.20 (s,2), 9.15 (s,2), 9.00(s,2), 8.70 (s,2), 6.90-7.60 (m,17), 4.80 (s,2), 5.00 (s,2) ppm;

3-(3-(3-amidino-6-methoxy)benzyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)-methyl!benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.30 (s,2), 9.20 (s,2), 8.90(s,2), 8.80 (s,2), 7.00-7.70 (m, 17), 5.00(s,2), 4.90 (s,2), 3.70 (s,3)ppm;

4,4'-bis (methoxy)-3,3'-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)-bis(methylene)!bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.20 (s,4), 8.80 (s,4),7.10-7.70 (m,16), 4.80 (s,4), 3.70 (s,3) ppm;

4,4'-bis(hydroxy)-3,3'-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)-bis(methylene)!bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 10.90 (s,2), 9.10 (s,4), 8.80(s,4), 6.90-7.60 (m,16), 4.80 (s,4) ppm;

3,3'-(2,3-dihydro-4,5-dimethyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzamidine);NMR (DMSO-d₆) 9.40 (s,4), (9.20 (s,4), 7.40-7.80 (m,8), 4.90 (s,4), 1.90(s,6) ppm;

3,3'-(4,4,7,7-tetramethyl-2-oxo-1,3-diazahepta-1,3-diyl)bis(methylene)!-bis(benzamidine);m.p. 247°-249° C.;

3,3'- (2-oxo-1,3-diazahepta-1,3-diyl)bis(methylene)!bis(benzamidine);NMR (DMSO-d₆) 9.40 (br,8), 7.40-7.80 (m,8), 4.50 (s,4), 3.20 (br,4),1.60 (b,4) ppm; m.p. 109°-111° C.;

4,4'- (2-oxo-1,3-diazapenta-1,3-diyl)bis(methylene)!bis(benzamidine);NMR (DMSO-d₆) 9.30 (s,4), 9.20 (s,4), 7.80 (d,4), 7.60 (d,4), 4.30(s,4), 3.20 (br,4), 1.60 (br,4) ppm; and

4-methoxy-3-(3-(3-dimethylaminocarbonylphenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl!benzonitrile;NMR (DMSO-d₆) 9.25 (s,4), 8.80 (s,4), 7.00-7.70 (m,17), 4.80 (s,2), 4.82(s,2), 3.70 (s,6).

EXAMPLE 2 4,4'-(1,2-Dihydro-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!bis(benzamidine),Methanesulfonic Acid Salt

A. In a manner similar to Example 1 above, 4,4'-(1,2-dihydro-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!bis(benzonitrile)(1.6 g, 4.4 mmol) was reacted sequentially with hydrochloric acid andethanolic ammonia. The resulting solid was dissolved in water andfree-based with sodium hydroxide (aq). The solid was collected byfiltration and dissolved in methanol. Methanesulfonic acid was added tothe solution (1:1 equivalent/amidine), followed by ether untilcrystallization. The crystals were collected by filtration and dried togive 4,4'-(1,2-dihydro-2-oxo-1H-benzimidazol-1,3-diyl)bis(methylene)!bis(benzamidine),methanesulfonic acid salt; NMR (DMSO-d₆) 9.3 (s,4), 9.0 (s,4), 7.8(d,4), 7.55 (d,4), 7.1 (m,2), 7.0 (m,2); 5.22 (s,4), 2.5 (s,6) ppm.

B. In a similar manner, the following compounds were made:

3,3'- (2-oxoimidazolin-1,3-diyl)bis(methylene)!bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.35 (s,4), 9.05 (s,4), 7.7 (m,4), 7.6(d,4), 4.42 (s,4), 3.25 (s,4), 2.5 (s,6)ppm;

3,3'-(2-oxo-4,4,5,5-tetramethylimidazolin-1,3-diyl)bis(methylene)!bis(benzamidine),methanesulfonic acid salt; NMR (DMSO-d₆) 9.25 (s,4), 8.9 (s,4), 7.73(s,2), 7.65 (m,4), 7.5 (t,2), 4.35 (s,4), 2.55 (s,6), 1.0 (s,12) ppm;

4,4'-(2-oxo-4,4,5,5-tetramethylimidazolin-1,3-diyl)bis(methylene)!bis(benzamidine),methanesulfonic acid salt; and

3,3'-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!-bis(benzamidine),methanesulfonic acid salt; NMR (DMSO-d₆) 9.25 (s,4), 8.98 (s,4), 7.65(d,2), 7.5 (m,4), 7.1-7.3 (m,12), 4.95 (s,4), 2.5 (s,6) ppm.

EXAMPLE 3 3,3'-(2,3-Dihydro-4-ethyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!bis(benzamidine),Trifluoroacetic Acid Salt

To 50% aqueous sodium hydroxide was added 1,3-bis3-(amidino)benzyl!-1,2-dihydro-5-ethyl-2-oxo-1H-imidazole-4-carboxylicacid, methyl ester, dihydrochloride (0.20 g, 0.46 mmol). After stirringfor 30 minutes, carbon dioxide (g) was bubbled through the solution toneutralize excess hydrochloride and methanol (1 mL) was added. The solidwas removed by filtration and the flitrate was concentrated in vacuo.After adjusting the pH to 6 with 3N hydrochloric acid (aq), the materialwas purified by high performance liquid chromatography (HPLC) to give3,3'-(2,3-dihydro-4-ethyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.4 (s,4), 9.35 (s,4), 7.65(d,2), 7.4-7.9 (m,8), 6.35 (s,1), 4.95 (s,2), 4.9 (s,2), 2.3 (q,2), 1.05(t,3) ppm.

EXAMPLE 4 1,3-Bis3-(amidino)benzyl!-1,2-dihydro-2-oxo-1H-imidazole-4,5-dicarboxylic Acid,Dihydrochloride

To 1,3-bis3-(amidino)benzyl!-1,2-dihydro-2-oxo-1H-imidazole-4,5-dicarboxylic acid,diethyl ester, dihydrochloride (0.1 g, 0.20 mmol) in methanol (1mL)/water (1 mL) at 0° C. was added 50% aqueous sodium hydroxide (2 mL).After stirring for 2 hours, the pH was adjusted to 1 with 3Nhydrochloric acid (aq). The resulting material was filtered and driedunder vacuum to give 1,3-bis3-(amidino)benzyl!-1,2-dihydro-2-oxo-1H-imidazole-4,5-dicarboxylic acid,dihydrochloride; NMR (DMSO-d₆) 9.35 (s,4), 9.0 (s,4), 7.7 (m,4), 7.58(m,4), 5.35 (s,4) ppm.

EXAMPLE 5

This example illustrates the preparation of representativepharmaceutical compositions for oral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g., 3,3 '-(1,2-dihydro-2-oxo-4,5,6,7-tetrachloro-1H-benzimidazol-1,3-diyl)bis(methylene)!bis(benzamidine):

    ______________________________________                                        A.        Ingredients     % wt./wt.                                           ______________________________________                                                Compound of the invention                                                                   20.0%                                                           Lactose       79.5%                                                           Magnesium stearate                                                                           0.5%                                                   ______________________________________                                    

The above ingredients are mixed and dispensed into hard-shell gelatincapsules containing 100 mg each, one capsule would approximate a totaldaily dosage.

    ______________________________________                                        B.        Ingredients     % wt./wt.                                           ______________________________________                                                Compound of the invention                                                                   20.0%                                                           Magnesium stearate                                                                          0.9%                                                            Starch        8.6%                                                            Lactose       79.6%                                                           PVP (polyvinylpyrrolidine)                                                                  0.9%                                                    ______________________________________                                    

The above ingredients with the exception of the magnesium stearate arecombined and granulated using water as a granulating liquid. Theformulation is then dried, mixed with the magnesium stearate and formedinto tablets with an appropriate tableting machine.

    ______________________________________                                        C.        Ingredients                                                         ______________________________________                                                Compound of the invention                                                                   0.1       g                                                     Propylene glycol                                                                            20.0      g                                                     Polyethylene glycol 400                                                                     20.0      g                                                     Polysorbate 80                                                                              1.0       g                                                     Water         q.s. 100 mL                                             ______________________________________                                    

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity ofwater is then added with stirring to provide 100 mL of the solutionwhich is filmred and bottled.

    ______________________________________                                        D.        Ingredients     % wt./wt.                                           ______________________________________                                                Compound of the invention                                                                   20.0%                                                           Peanut Oil    78.0%                                                           Span 60        2.0%                                                   ______________________________________                                    

The above ingredients are melted, mixed and filled into soft elasticcapsules.

    ______________________________________                                        E.        Ingredients     % wt./wt.                                           ______________________________________                                                Compound of the invention                                                                   1.0%                                                            Methyl or carboxymethyl                                                                     2.0%                                                            cellulose                                                                     0.9% saline   q.s. 100 mL                                             ______________________________________                                    

The compound of the invention is dissolved in the cellulose/salinesolution, filtered and bottled for use.

EXAMPLE 6

This example illustrates the preparation of a representativepharmaceutical formulation for parenteral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g., 3,3'-(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)!bis(benzamidine):

    ______________________________________                                        Ingredients                                                                   ______________________________________                                        Compound of the invention                                                                       0.02        g                                               Propylene glycol  20.0        g                                               Polyethylene glycol 400                                                                         20.0        g                                               Polysorbate 80    1.0         g                                               0.9% Saline solution                                                                            q.s. 100 mL                                                 ______________________________________                                    

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity of0.9% saline solution is then added with stirring to provide 100 mL ofthe I.V. solution which is filtered through a 0.2 μ membrane filter andpackaged under sterile conditions.

EXAMPLE 7

This example illustrates the preparation of a representativepharmaceutical composition in suppository form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,3,3'-2,3-dihydro-4-(4-dimethylaminophenyl)-2-oxo-5-phenyl-1H-imidazol-1,3-diyl!bis(methylene)!bis(benzamidine):

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                         1.0%                                                      Polyethylene glycol 1000                                                                         74.5%                                                      Polyethylene glycol 4000                                                                         24.5%                                                      ______________________________________                                    

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

EXAMPLE 8

This example illustrates the preparation of a representativepharmaceutical formulation for insuffiation containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g., 7- 3-4-(amidino)benzyl!-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl!methyl!-naphthalene-2-carboximidamide:

    ______________________________________                                        Ingredients           % wt./wt.                                               ______________________________________                                        Micronized compound of the invention                                                                 1.0%                                                   Micronized lactose    99.0%                                                   ______________________________________                                    

The ingredients are milled, mixed, and packaged in an insufflatorequipped with a dosing pump.

EXAMPLE 9

This example illustrates the preparation of a representativepharmaceutical formulation in nebulized form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g., 7-3-3-(amidino)benzyl!-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl!methyl!naphthalene-2-carboximidamide:

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                         0.005%                                                    Water              89.995%                                                    Ethanol            10.000%                                                    ______________________________________                                    

The compound of the invention is dissolved in ethanol and blended withwater. The formulation is then packaged in a nebulizer equipped with adosing pump.

EXAMPLE 10

This example illustrates the preparation of a representativepharmaceutical formulation in aerosol form containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g., 7,7'-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl!bis(methylene)!bis(naphthalene-2-carboximidamide):

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                        0.10%                                                      Propellant 11/12   98.90%                                                     Oleic acid         1.00%                                                      ______________________________________                                    

The compound of the invention is dispersed in oleic acid and thepropellants. The resulting mixture is then poured into an aerosolcontainer fitted with a metering valve.

EXAMPLE 11 (In Vitro Assay for Factor Xa and Thrombin)

This assay demonstrates the activity of the compounds of the inventiontowards factor Xa, thrombin and tissue plasminogen activator. Theactivities were determined as an initial rate of cleavage of the peptidep-nitroanilide by the enzyme. The cleavage product, p-nitroaniline,absorbs at 405 nm with a molar extinction coefficient of 9920M⁻¹ cm⁻¹.

Reagents and Solutions:

Dimethyl sulfoxide (DMSO) (Baker analyzed grade).

Assay buffer:

50 mM TrisHCl, 150 mM NaCl, 2.5 mM CaCl₂, and 0.1% polyethylene glycol6000, pH 7.5.

Enzymes (Enzyme Research Lab.):

1. Human factor Xa stock solution: 0.281 mg/mL in assay buffer, storedat -80° C. (working solution (2X): 106 ng/mL or 2 nM in assay buffer,prepared prior to use).

2. Human thrombin stock solution: Stored at -80° C. (working solution(2X): 1200 ng/mL or 40 nM in assay buffer, prepare prior to use).

3. Human tissue plasminogen activator (tPA) (Two chains, Sigma) stocksolution: 1 mg/mL, stored at -80° C. (working solution (2X): 1361 ng/mLin assay buffer, prepare prior to use).

Chromogenic substrates (Pharmacia Hepar Inc.):

1. S2222 (FXa assay) stock solution: 6 mM in dH₂ O, store at 4° C.(working solution (4X): 656 μM in assay buffer).

2. S2302 (Thrombin assay) stock solution: 10 mM in dH₂ O, stored at 4°C. (working solution (4X): 1200 μM in assay buffer).

3. S2288 (tPA assay) stock solution: 10 mM in dH₂ O, stored at 4° C.(working solution (4X): 1484 μM in assay buffer). (All substrate workingsolutions were prepared on assay day 5.)

Standard inhibitor compound stock solution:

5 mM in DMSO, stored at -20° C.

Test compounds (compounds of the invention) stock solutions:

10 mM in DMSO, stored at -20° C.

Assay procedure:

Assays were performed in 96-well microtiter plates in a total volume of200 μl. Assay conducted in final concentration of 50 mM TrisHCl, 150 mMNaCl, 2.5 mM CaCl₂, 0.1% polyethylene glycol 6000, pH 7.5, in theabsence or presence of the standard inhibitor or the test compounds andenzyme and substrate at following concentrations: (1) 1 nM factor Xa and164 μM S2222; (2) 20 nM thrombin and 300 S2302; and (3) 10 nM tPA and371 μM S2288. Concentrations of the standard inhibitor compound in theassay were from 5 μM to 0.021 μM in 1 to 3 dilution. Concentration ofthe test compounds in the assay typically were from 10 μM to 0.041 μM in1 to 3 dilution. For potent test compounds, the concentrations used inthe factor Xa assay were further diluted 100 fold (100 nM to 0.41 nM) or1000 fold (10 nM to 0.041 nM). All substrate concentrations used areequal to their K_(m) values under the present assay conditions. Assayswere performed at ambient temperature.

The first step in the assay was the preparation of 10 mM test compoundstock solutions in DMSO (for potent test compounds, 10 mM stocksolutions were further diluted to 0.1 or 0.01 mM for the factor Xaassay), followed by the preparation of test compound working solutions(4X) by a serial dilutions of 10 mM stock solutions with Biomek 1000 (orMultiprobe 204) in 96 deep well plates as follows:

(a) Prepare a 40 μM. working solution by diluting the 10 mM stock 1 to250 in assay buffer in 2 steps: 1 to 100, and 1 to 2.5.

(b) Make another five serial dilutions (1:3) of the 40 μM solution (600μl for each concentration). A total of six diluted test compoundsolutions were used in the assay.

Standard inhibitor compound (5 mM stock) or DMSO (control) went throughthe same dilution steps as those described above for test compounds.

The next step in the assay was to dispense 50 μl of the test compoundworking solutions (4X) (from 40 uM to 0.164 uM), in duplicate, tomicrotiter plates with Biomek or MP204. To this was added 100 μl ofenzyme working solution (2X) with Biomek or MP204. The resultingsolutions were incubated at ambient temperature for 10 minutes.

To the solutions was added 50 μl of substrate working solution (4X) withBiomek or MP204.

The enzyme kinetics were measured at 405 nm, at 10 seconds interval, forfive minutes in a THERMOmax plate reader at ambient temperature.

Calculation of K_(i) of the BX compounds:

Enzyme rates were calculated as mOD/min based on the first two minutesreadings. The IC₅₀ values were determined by fitting the data to thelog-logit equation (linear) or the Morrison equation (non-linear) withan EXCEL spread-sheet. Ki values were then obtained by dividing the IC₅₀by 2. Routinely, Ki(factor Xa) values lower than 3 nM were calculatedfrom the Morrison equation.

Compounds of the invention, when tested in this assay, demonstrated theability to inhibit human factor Xa and human thrombin.

EXAMPLE 12 (In Vitro Assay for Human Prothrombinase)

This assay demonstrates the ability of the compounds of the invention toinhibit prothrombinase. Prothrombinase (PTase) catalyzes the activationof prothrombin to yield fragment 1.2 plus thrombin with meizothrombin asthe intermediate. This assay is an end point assay. Activity of theprothrombinase is measured by activity of thrombin (one of the reactionproducts) or by the amount of thrombin formed/time based on a thrombinstandard curve (nM vs mOD/min). For determination of IC₅₀ (PTase) of thecompounds of the invention, PTase activity was expressed by thrombinactivity (mOD/min).

Materials:

Enzymes:

1. Human factor Va (Haematologic Technologies Inc., Cat#HCVA-0110)working solution: 1.0 mg/mL in 50% glycerol, 2 mM CaCl₂, stored at -20°C.

2. Human factor Xa (Enzyme Res. Lab. cat#HFXa1011) working solution:0.281 mg/mL in assay buffer (without BSA), stored at -80° C.

3. Human prothrombin (FII) (Enzyme Res. Lab., Cat#HP1002) workingsolution: Diluted FII to 4.85 mg/mL in assay buffer (without BSA),stored at -80° C.

Phospholipid (PCPS) vesicles:

PCPS vesicles (80%PC, 20%PS) were prepared by modification of the methodreported by Barenholz et al., Biochemistry (1977), Vol. 16, pp.2806-2810.

Phosphatidyl serine (Avanti Polar Lipiris, Inc., Cat#840032):

10 mg/mL in chloroform, purified from brain, stored -20° C. undernitrogen or argon.

Phosphatidyl Choline (Avanti Polar Lipids, Inc., Cat#850457):

50 mg/ml in chloroform, synthetic 16:0-18:1 Palmitoyl-Oleoyl, stored at-20° C. under nitrogen or argon.

Spectrozyme-TH (American Diagnostica Inc., Cat#238L, 50 μmoles, storedat room temperature) working solution: Dissolved 50 μmoles in 10 mL dH₂O.

BSA (Sigma Chem Co., Cat#A-7888, FractionV, RIA grade).

Assay buffer: 50 mM TrisHCl, pH 7.5, 150 mM NaCl, 2.5 mM CaCl₂, 0.1% PEG6000 (BDH), 0.05% BSA (Sigma, Fr.V, RIA grade).

For one plate assay, prepare the following working solutions:

1. Prothrombinase complex:

(a) 100 μM PCPS (27.5 μl of PCPS stock (4.36 mM) diluted to final 1200μl with assay buffer.

(b) 25 nM Human factor Va: 5.08 μl of Va stock(1 mg/mL) was diluted tofinal 1200 μl with assay buffer.

(c) 5 pM Human factor Xa: Dilute Xa stock (0.281 mg/mL) 1:1,220,000 withassay buffer. Prepare at least 1200 μl.

Combine equal volumes (1100 μl) of each component in the order of PCPS,factor Va and factor Xa. Let stand at ambient temperature for 5 to 10minutes and use immediately, or store in ice (bring to ambienttemperature before use).

2. 6μM Human prothrombin (FII): dilute 124 μL of FII stock (4.85 mg/mL)to final 1400 μL with assay buffer.

3. 20 mM EDTA/Assay buffer: 0.8 mL of 0.5 M EDTA (pH 8.5) plus 19.2 ml,assay buffer.

4. 0.2 mM Spectrozyme-TH/EDTA buffer: 0.44 mL of SPTH stock (5 mM) plus10.56 mL of 20 mM EDTA/assay buffer.

5. Test compounds (compounds of the invention):

Prepare a working solution (5X) from 10 mM stock (DMSO) and make aseries of 1:3 dilution. Compounds were assayed at 6 concentrations induplicate.

Assay conditions and procedure:

Prothrombinase reaction was performed in final 50 μL of mixturecontaining PTase (20 uM PCPS, 5 nM hFVa, and 1 pM hFXa), 1.2 uM humanfactor II and varied concentration of the test compounds (5 μM to 0.021μM or lower concentration range). Reaction was started by addition ofPTase and incubated for 6 minutes at room temperature. Reaction wasstopped by addition of EDTA/buffer to final 10 mM. Activity of thrombin(product) was then measured in the presence of 0.1 mM of Spectrozyme-THas substrate at 405 nm for 5 minutes (10 second intervals), at ambienttemperature, in a THEROmax microplate reader. Reactions were performedin 96-well microtiter plates.

In the first step of the assay, 10 μl of diluted test compound (5X) orbuffer was added to the plates in duplicate. Then 10 μl of prothombin(hFII) (5X) was added to each well. Next 30 μl PTase was added to eachwell, mix for about 30 seconds. The plates were then incubated atambient temperature for 6 minutes.

In the next step, 50 μl of 20 mM EDTA (in assay buffer) was added toeach well to stop the reaction. The resulting solutions were then mixedfor about 10 seconds. Then 100 μl of 0.2 mM spectrozyme was added toeach well. The thrombin reaction rate was then measured at 405 nm for 5minutes (at 10 second intervals) in a Molecular Devices microplatereader.

Calculations:

Thrombin reaction rate was expressed as mOD/minute using OD readingsfrom the five minute reaction. IC₅₀ values were calculated with thelog-logit curve fit program.

The compounds of the invention demonstrated the ability to inhibitthrombinase when tested in this assay.

EXAMPLE 13 (In Vivo Assay)

The following assay demonstrates the ability of the compounds to act asanti-coagulants.

Male rats (250-330 g) were anesthetized with sodium pentobarbital (90mg/kg, i.p.) and prepared for surgery. The left carotid artery wascannulated for the measurement of blood pressure as well as for takingblood samples to monitor clotting variables (prothrombin time (PT) andactivated partial thromboplastin time (aPTT)). The tail vein wascannulated for the purpose of administering the test compounds (i.e.,the compounds of the invention and standards) and the thromboplastininfusion. The abdomen was opened via a mid-line incision and theabdominal vena cava was isolated for 2-3 cm distal to the renal vein.All venous branches in this 2-3 cm segment of the abdominal vena cavawere ligated. Following all surgery, the animals were allowed tostabilize prior to beginning the experiment. Test compounds wereadministered as an intravenous bolus (t=0). Three minutes later (t=3), a5-minute infusion of thromboplastin was begun. Two minutes into theinfusion (t=5), the abdominal vena cava was ligated at both the proximaland distal ends. The vessel was left in place for 60 minutes, afterwhich it was excised from the animal, slit open, the clot (if any)carefully removed, and weighed. Statistical analysis on the results wasperfomed using a Wilcoxin-matched-pairs signed rank test.

The compounds of the invention, when tested in this assay, demonstratedthe ability to clot the blood.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made and equivalentsmay be substituted without departing from the true spirit and scope ofthe invention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound of formula (II): ##STR11## wherein: Ais --C(R⁵)(R⁶)--CH₂ --CH₂ --C(R⁹)(R¹⁰)--;R¹ is --C(NH)NH₂,--C(NH)N(H)OR¹¹, --C(NH)N(H)C(O)R⁹, or --C(NH)N(H)C(O)OR¹¹ ; R² and R³are the same or different and are selected from the group consisting ofindependently hydrogen, halo, lower alkyl, lower haloalkyl, phenyl,naphthyl, --OR¹¹, --C(O)OR¹¹, --C(O)N(R¹¹)R¹², --N(R¹¹)R¹²,--N(H)C(O)R¹¹, and --N(H)S(O)₂ R¹¹ ; R⁴ is halo, lower haloalkyl,imidazolyl, --C(NH)NH₂, --C(NH)NHOR¹¹, --C(NH)N(H)C(O)R⁹,--C(NH)N(H)C(O)OR¹¹, --OR¹¹, --C(O)R¹³, --(CH₂)_(n) C(O)OR¹¹ (where n is0 to 6), --C(O)N(R¹¹)R¹², or --N(R¹¹)R¹² ; R⁵, R⁶, R⁹ and R¹⁰ areindependently hydrogen, halo, lower alkyl, lower haloalkyl, 4-pyridinyl,--OR¹¹, --C(O)OR¹¹, --C(O)N(R¹¹)R¹², phenyl (optionally substituted byone or more substituents selected from the group consisting of halo,hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R¹¹)R¹²), ornaphthyl (optionally substituted by one or more substituents selectedfrom the group consisting of halo, hydroxy, lower alkyl, lowerhaloalkyl, lower alkoxy and --N(R¹¹)R¹²); R¹¹ and R¹² are independentlyhydrogen, lower alkyl, phenyl, naphthyl or lower aralkyl; and R¹³ ispyrrolidinyl, 4-morpholinyl, piperazinyl, N-methylpiperazinyl, orpiperidinyl; or a pharmaceutically acceptable salt thereof.
 2. Apharmaceutical composition useful in treating a human having adisease-state characterized by thrombotic activity, which compositioncomprises a therapeutically effective amount of a compound of formula(II): ##STR12## wherein: A is --C(R⁵)(R⁶)--CH₂ --CH₂ C(R⁹)(R¹⁰)--;R¹ is--C(NH)NH₂, --C(NH)N(H)OR¹¹, --C(NH)N(H)C(O)R⁹, or --C(NH)N(H)C(O)OR¹¹ ;R² and R³ are the same or different and are selected from the groupconsisting of independently hydrogen, halo, lower alkyl, lowerhaloalkyl, phenyl, naphthyl, --OR¹¹, --C(O)OR¹¹, --C(O)N(R¹¹)R¹²,--N(R¹¹)R¹², --N(H)C(O)R¹¹, and --N(H)S(O)₂ R¹¹ ; R⁴ is halo, lowerhaloalkyl, imidazolyl, --C(NH)NH₂, --C(NH)NHOR¹¹, --C(NH)N(H)C(O)R⁹,--C(NH)N(H)C(O)OR¹¹, --OR¹¹, --C(O)R¹³, --(CH₂)_(n) C(O)OR¹¹ (where n is0 to 6), --C(O)N(R¹¹)R¹², or --N(R¹¹)R¹² ; R⁵, R⁶, R⁹ and R¹⁰ areindependently hydrogen, halo, lower alkyl, lower haloalkyl, 4-pyridinyl,--OR¹¹, --C(O)OR¹¹, --C(O)N(R¹¹)R¹², phenyl (optionally substituted byone or more substituents selected from the group consisting of halo,hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R¹¹)R¹²), ornaphthyl (optionally substituted by one or more substituents selectedfrom the group consisting of halo, hydroxy, lower alkyl, lowerhaloalkyl, lower alkoxy and --N(R¹¹)R¹²); R¹¹ and R¹² are independentlyhydrogen, lower alkyl, phenyl, naphthyl or lower aralkyl; and R¹³ ispyrrolidinyl, 4-morpholinyl, piperazinyl, N-methylpiperazinyl, orpiperidinyl; or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.